chr7-100827002-G-T

Position:

• chr7-100827002-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004444.5(EPHB4):​c.29C>A​(p.Ala10Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPHB4 NM_004444.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.498

Genes affected

EPHB4 (HGNC:3395): (EPH receptor B4) Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene binds to ephrin-B2 and plays an essential role in vascular development. [provided by RefSeq, Jul 2008]

EPHB4 (HGNC:):

SLC12A9 (HGNC:17435): (solute carrier family 12 member 9) Predicted to enable potassium:chloride symporter activity. Predicted to be involved in cell volume homeostasis; inorganic ion homeostasis; and inorganic ion transmembrane transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHB4	NM_004444.5	c.29C>A	p.Ala10Asp	missense_variant	1/17	ENST00000358173.8	NP_004435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8	c.29C>A	p.Ala10Asp	missense_variant	1/17	1	NM_004444.5	ENSP00000350896.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426456 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 707076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000207 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 29, 2020

The EPHB4 c.29C>A; p.Ala10Asp variant, to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at codon 10 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.505). However, due to limited information, the clinical significance of the p.Ala10Asp variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;.
Eigen	Benign	0.093
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.4	.;L;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Uncertain	0.51
Sift	Benign	0.058	T;T;.
Sift4G	Benign	0.12	T;T;T
Polyphen		0.96	P;D;.
Vest4		0.74
MVP		0.78
MPC		1.2
ClinPred		0.64	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.13
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1429727921; hg19: chr7-100424624;